Fine-tuning of cell signaling by glypicans

Abstract

Signaling peptides of the extracellular environment regulate cell biological processes underlying embryonic development, tissue homeostasis, and pathophysiology. The heparan sulphate proteoglycans, glypicans, have evolved as essential modulators of key regulatory proteins such as Wnt, Bmp, Fgf, and Shh. By acting on signal spreading and receptor activation, glypicans can control signal read-out and fate in targeted cells. Genetic and embryological studies have highlighted that glypicans act in a temporal and spatially regulated manner to modulate distinct cellular events. However, alterations of glypican function underlie human congenital malformations and cancer. Recent reports are starting to reveal their mechanism of action and how they can ensure tight modulation of cell signaling.

Fig. 1

Schematic representation of glypican structure and potential mechanism of action. Left the glypican core proteins, located in the extracellular matrix, consist of a cysteine-rich domain (CRD) possibly forming a globular structure stabilized by disulphide bridges. Glypicans are bound to the cell membrane by a glycosylphosphatidylinositol (GPI) linkage. HS chains are linked to serine residues adjacent to the plasma membrane (adapted from De Cat et al. [6]). Proteolytic cleavages of glypicans either downstream of the CRD or at the level of the GPI would give rise to additional glypican forms. Right glypicans can function as classical co-receptors by favoring signal/ligand dimerization, ligand binding to the cell membrane high-affinity receptor, and in stabilizing the ligand-receptor complex. Alternatively, glypicans may control signal diffusion. Potential involved mechanisms include (1) shedding of glypicans from the plasma membrane, (2) binding of extracellular signals to favor two-dimensional ‘sliding’ along the HS chains, (3) lipid rafts, and (4) vesicular transport